Good afternoon. I'm Geulah Livshits, and it's now my pleasure to introduce Dr. Igor Bilinsky, Chief Operating Officer of Iovance Therapeutics. The format for this session is roughly a 25-minute fireside chat. If you have any questions, feel free to type them into the question box, and we'll try to ask them on your behalf. Thanks for joining us. Earlier this year, Iovance received the landmark approval of Amtagvi, the first cell therapy for a solid tumor, which was a major achievement for the company and the cell therapy space. To orient us all, can you first please give us an overview of Iovance's TIL programs and the company's strategic approach to manufacturing? Happy to, and good afternoon, Geulah. Good to be here. So Iovance is a commercial-stage immuno-oncology company. Our mission is to innovate, develop, and deliver TIL therapies for patients with cancer. TIL therapy or TIL cell therapy is a new approach that deploys patient-specific T cells, called tumor-infiltrating lymphocytes, or TIL, to fight cancer. It is a one-time treatment that is manufactured using a proprietary process to collect, isolate, and multiply into billions patients' unique T cells from a portion of their tumor. Unlike other cell therapy approaches that target shared antigens among patients, TIL cell therapy is by design polyclonal and individualized for each patient based on their own unique neoantigen profile. So in February of this year, we received our lead product, Amtagvi, lifileucel, received the first FDA approval, and it's the first FDA-approved T-cell therapy for a solid tumor cancer indication. Amtagvi is indicated for treatment of patients with advanced post-PD-1 melanoma. It is the first FDA approval in the treatment setting, and the unmet medical need is high. About 28,000 patients with melanoma die annually in the U.S. Our immediate priority is to successfully commercialize Amtagvi, and the launch is going very well. We started with about 30 Authorized Treatment Centers at the time of approval and are now expanding that to approximately 50 total ATCs by the end of May. And then to introduce Amtagvi outside the U.S., we also plan to submit MAA for approval in the EU in the first half of this year and applications for approval in Canada and the U.K. in the second half of this year. These geographic expansions together are expected to more than double the addressable patient population in post-PD-1 advanced melanoma. Our strategy beyond the initial launch in post-PD-1 melanoma is focused on three general areas. One is expansion to other tumor types, such as non-small cell lung cancer, where we are conducting a pivotal study, IOV-LUN-202, or endometrial cancer. The second one is expansion to earlier lines of therapy, such as frontline melanoma, where we are conducting a pivotal global phase III study, TILVANCE-301. And the third area is development of next generations of TIL technologies, such as PD-1-inactivated TIL, IOV-4001, that is now in the clinic or cytokine-tethered TILs that are in preclinical development. And for all of these programs, overall manufacturing is a core competency for Iovance, and we built our own manufacturing facility, Iovance Cell Therapy Center, or ICTC, in Philadelphia. That facility is now FDA-approved for commercial manufacturing of Amtagvi, and it also serves patients in our clinical trials in melanoma, lung cancer, other indications in the U.S., in Europe, and in other geographies. So this year, 2024, has been a very exciting year for Iovance so far. Great. So let's touch on a little bit your current process that you're using. That's the Gen 2 process. We've talked about how in and of itself it's a 22-day process. Can you tell us a little bit about what the total tumor to vein time, including things like release testing, has been? When we received the approval earlier this year, we guided to about 34 days from receipt of tumor tissue at our manufacturing facility to return shipment of Amtagvi to the ATC, followed by lymphodepletion prior to infusion. And that's the number we're tracking to. And just as a reminder, in the commercial setting, there's more flexibility for providing a patient with bridging therapy, which is not possible in a clinical trial setting, of course. So turning to the overall process that you've just gone through, can you talk about what learnings you took away from the BLA process, the FDA pre-license inspection, review process, et cetera, regarding CMC in general, and that you could apply toward your ongoing programs that you talked about in lung cancer and other indications? So we've worked closely with the FDA on CMC topics over the past few years, and in particular, on the potency assay topics. The FDA, by now, is very familiar with our manufacturing process at Iovance and manufacturing approaches after reviewing and approval the BLA for Amtagvi. The potency assay matrix for lifileucel, which we initially developed for melanoma, provides a clear template blueprint for other TIL programs in other indications, such as lung cancer. Supported by. What I, I'd also like to note is that supported by the successful BLA review and successful pre-license inspections, we launched Amtagvi out of two manufacturing facilities, not just one. Having two facilities, ICTC and our contract manufacturer, provides us with a lot of additional flexibility for the commercial launch in melanoma, as well as clinical trials in melanoma and other indications. A lot of the learnings from the FDA discussions on the melanoma BLA are now directly translatable to a regulatory dossier in other countries, such as the MAA submission we're working on, and other indications such as lung cancer, because they use the same Gen 2 manufacturing process as the process approved for Amtagvi in the U.S. So we expect to have very similar CMC sections in future supplemental BLAs and other indications such as lung, as well as in ex-U.S. submissions, such as the MAA filing in Europe that we're working on for this quarter. Mm-hmm. So on the ex-U.S. side, maybe this is what you just alluded to, but any comments on feedback that you've received from ex-U.S. regulators? Ex-U.S., we're very pleased with our discussions, progress with ex-U.S. submissions. We are focusing on countries with the high prevalence of melanoma, as well as those countries that have existing reimbursement for cell therapies. Our planned regulatory submissions in the EU this quarter and in Canada and the U.K., second half of the year, are on track. These dossiers are based on many successful interactions with regulatory authorities in these geographies, and for example, the EMA is aligned around the C-144-01 clinical trial to serve as the basis for the MAA submission. It's the same trial that served as the basis for our BLA approval in the U.S.. And so all of that, all of the ex-U.S. discussions are going very well and remain on track for the submission targets. Got it. So looking at the Amtagvi launch itself and onward, what is the current capacity at the ICTC for commercial and clinical manufacturing? So ICTC has built, has the capacity to provide TIL therapies for more than 2,000 patients per year, and we are ramping up staff as needed to match the combined commercial and clinical demand. Right now, we're staffed appropriately for launch, and we're continuing to ramp up staff in anticipation of growing demand. And of course, our contract manufacturer provides us with additional flexibility and capacity to supplement our internal capacity at ICTC. So that's currently. And can you talk a little bit about the kind of capacity that you could reach by building out within the shell of your current facility, and when that additional capacity could come online? So ICTC in the Philadelphia Navy Yard, it's the facility is approximately 136,000 sq ft in size, and part of that initial construction left shell space open, and we are now we have initiated the build-out of that shell space in preparation for growing demand, expanding to both in the U.S. and expanding to other geographies and our advancing pipeline. That shell space build-out is expected to take a couple of years and is expected to enable ICTC to supply TIL therapies for over 5,000 patients annually when the construction and the qualification is completed in a couple of years. Can you elaborate on the kind of flexibility that you have to expand further beyond that? So beyond that, we are looking at multiple options. One option, actually, is to construct another building adjacent to ICTC in the Philadelphia Navy Yard. We have an option to do that. And so that, for example, together with investments in manufacturing process automation, is expected to bring our internal manufacturing capacity to supply TIL for over 10,000 patients annually. Alright 10,000. And that's something that you would potentially invest in, I guess, after the build-out of the initial shell, so that's a longer term vision? It's. That project is a longer-term project, which we're actually starting that right now, in part because it requires longer lead times. So, the work on that and design is beginning right now. We're not waiting for that because we do anticipate significant growth and demand in the coming years. And just like we invested in ICTC very early on to make sure that it's online. Right And ready for launch, similarly, we'd like to be ahead of the capacity, have our capacity planning way ahead of demand, so that we can always satisfy patient demand, both commercially and the clinical trials. Got it. That makes sense. So I guess in addition to space and equipment, we often hear about having a trained team of sufficient size that can be, that can actually execute as being important for the cell and gene therapy space. So how have you prepared for launch and, and onward on that front? Very important. I completely agree. So a strong manufacturing team is very important in biotech in general, but cell therapy in particular. Our CMC team, senior team, and then the junior, more junior team, has a lot of cell therapy experience and has successfully navigated Iovance through the FDA review and the BLA approval earlier this year. Right now, we're staffed appropriately for launch, and we are continuing the staffing ramp-up to meet the demand growth that we expect, both from patients in melanoma commercially, as well as our increasing demand in clinical trials. And as we continue to grow, we're fortunate to have ICTC located in Philadelphia, where we can tap into very significant talent pool with cell and gene therapy manufacturing experience, as well as the next generation of talent through local colleges and local schools and local resources that we're working very closely with in Philadelphia. In the past and also during this discussion, you talked about having flexible external capacity, including with your partner, WuXi. There has been some uncertainty there due to the BIOSECURE Act. It does seem like you have plenty of internal capacity for near-term use, but in general, do you anticipate a near-term impact on your ability to meet demand, and how are you thinking about that issue longer term? So we do not anticipate any significant impact of the BIOSECURE Act on our ability to manufacture and meet demand for Amtagvi and clinical trials if that BIOSECURE Act or its amended version becomes law. As I mentioned, ICTC is built to support several thousand patients annually, and we are currently working to expand that facility within the existing shell space to more than double the capacity. So we are very comfortable with our internal capabilities to address anticipated patient demand, both commercially and clinically. Got it. So maybe turning to the process itself, for TIL, the tumor harvest step itself, that can impact the quality of the TIL product, and that is something that's performed by individuals at the treatment center. Can you expand a little bit on the kind of training that you've been implementing at ATCs to ensure that part goes smoothly? So the training program, customized training program for tumor tissue procurement is an important part of our ATC onboarding process, and that includes working with surgeons to train them to identify appropriate lesions, appropriate anatomical sites for resection that optimize the quality and the quantity of the procured tumor for manufacturing. It also shares best practices in the lesion prosection after removal before it's transferred to the tumor shipment kit. And everything related to sample collection happens in the OR and minimizes the number of handoffs, number of people handling the sample. There's a paper published in 2022 on the surgical considerations of tumor tissue procurement for TIL, and that paper was the first author is Dr. Mullinax, and that was co-authored by a number of TIL KOLs, as well as Iovance subject matter experts. That paper also lays out best practices that minimize patient inconvenience, minimize patient morbidity, while optimizing tumor tissue quantity and quality for TIL manufacturing. That's very important. And again, that's a very important part of our onboarding for the ATCs that we work with commercially. And anything you can share regarding feedback that you've received from ATCs on this front? The feedback so far has been very positive. The medical affairs team at Iovance is led by very seasoned melanoma surgeons with many years of clinical experience at top hospitals prior to joining Iovance. And so that team is in close contact with surgeons at the ATCs to answer any questions that come up, provide immediate feedback, real time if needed. And again, so far, the feedback's been very positive from the ATCs on that. And there's also, I would highlight, there's a clearly very strong level of interest from the ATCs and the patients. When we received approval in February, the first patient underwent tumor procurement for manufacturing on the first business day of the approval, and the manufacturing started the next day. Right. Absolutely. And so in terms of the manufacturing itself, can you talk about the steps that you've taken to protect your supply chain? Supply chain, we think about that constantly. That's an important part of our business. One example perhaps is an acquisition of Proleukin last year, because Proleukin, or just IL-2, it's an important part of the TIL administration regimen that's given to patients after TIL infusion to help T cells proliferate. So we actually acquired that commercial product last year and now fully control that supply chain. And in general, we look at the supply chain weaknesses, potential vulnerabilities constantly. It's an ongoing process for us, and manage it by either identifying secondary suppliers, building inventories where necessary, putting together supply agreements. So the supply chain team has been working on that well in advance of launch and continues to monitor potential weaknesses and always look to be ahead of any supply issues that come up. Great. So as you mentioned earlier, you do have a number of other next gen TIL programs that incorporate variations on the process, I mean, gene editing, TIL selection, shorter duration, starting with a core biopsy, et cetera. So can you provide a little bit more context on these programs and explain how your manufacturing process can accommodate these modifications? So our next generation programs are focused on optimizing TIL and developing next generations of technology. The lead program in that group is IOV-4001, which is a PD-1 inactivated TIL. It's currently in the first in human clinical trial in the patients with advanced melanoma and advanced non-small cell lung cancer. In that program, during manufacturing process, we use TALEN technology licensed from Cellectis to inactivate PD-1 within TIL cells. otherwise, this TIL therapy follows the same approach as our gen two manufacturing process that we use for Amtagvi, that's commercially approved. Very similar, tumor tissue procurement, very similar manufacturing steps, but some addition related to PD-1 inactivation. Also in the pipeline, I think I mentioned we have, we're working on cytokine-tethered TILs to further improve TIL performance, and those programs are now advancing through preclinical development, and I expect we'll share more detail about those programs. We're very excited about them. We'll share more detail about them shortly as we have more data that's ready for presentation. And the manufacturing process, again, for IOV-4001, for other more advanced processes, our TIL manufacturing process remains very similar and accommodates these technologies with relatively minor additions or modifications. Got it. So even processes that take a shorter period of time or use a different starting material, such as core biopsy, still kind of slot into the overall workflow pretty similarly? A lot of the workflows are similar. The clean rooms we've designed that ahead of time, thinking a few steps ahead. So the clean rooms are designed with flexibility to accommodate potentially next generations of technology that are coming down the pipe. In terms of manufacturing success rate, you purported a generally high manufacturing success rate in your trials in melanoma. How much you expect that to vary across different indications or different patient settings, or just generally factors that might determine how that process goes in relation to the process and the patient? So in the commercial setting, it's too early to share the exact numbers, so we'll do so a bit later when appropriate. But in general, in the commercial setting, what you expect, similar to the benchmarks from CAR T companies, is that initially in the first quarter or two, one may see lower success rates, and then those typically improve in the back half of the year and beyond as the launch ramps up. So again, we'll see whether we follow the trend, but that's something that we generally expect. In the clinical trial setting, we've seen very similar manufacturing success rates across multiple indications, from melanoma to lung and beyond, and also across multiple patient settings, where for example, Amtagvi was approved based on the patient population with a median of three prior lines of therapy. We saw, we see a manufacturing success rate in that setting similar to frontline melanoma, where patients had fewer prior therapies. There's a lot of consistency, again, on the manufacturing process across indications and across patient demographics. Got it. And so one of the topics that has come up over the course of this summit and in general in conversations around manufacturing is having to balance leveraging a platform process that has been validated by regulators that enables you to continue to move quickly with incorporating new technological innovations that could improve product profiles or things like manufacturing efficiency. So how is Iovance approaching this issue? That is an important part of our longer term planning and something, again, the team is working on very actively right now. One area we believe is important is manufacturing automation, and that will become increasingly important for scaling up our manufacturing capacity to provide TIL therapies to tens of thousands of patients with cancer annually. And so that's one area. In addition, of course, we're working on next gen TILs such as cytokine-secreting TILs, PD-1, and other knockout TILs that would then employ some of these manufacturing innovations in addition to the technology innovations at the same time. But again, automation, I would name, that probably is the number one long-term investment we need to make to bring really be able to bring TIL to tens of thousands of patients annually, which is the potential of this platform. Is that kind of part of the vision of that second wave of expansion in the additional building, or? We expect, yes. So to get to 10,000 and above, we'll need to combine both an additional facility and new manufacturing automation technologies. And again, both are i n the early, well, not the early stages of development right now. Got it. And so lastly, touching on COGS, I'm sure you can't get too specific, but what can you share regarding where COGS are now and how that might evolve over time, as you go along? So directionally, again, we're, we're not sharing the exact numbers yet. We'll do so once we start announcing revenues. But for now, COGS we expect to be similar to CAR T directionally because the labor intensity of the technologies are similar. And one difference is, TIL does not use viral vectors, so that's one difference, one subtraction perhaps we'd expect on the COGS. Overall, as typical in manufacturing, as typical for other cell therapies, we expect that the cost of goods will continue to improve over time as a function of the scale curve and the experience curve. As we add efficiencies and process improvements in manufacturing, as well as with higher commercial volumes, higher capacity utilization of our manufacturing facility, we expect COGS to be continuously decreasing. So you mentioned you don't have, obviously, don't incorporate a viral vector in here. So, any comments on what the major COGS drivers are in your process? I mean, it's very similar to CAR T with the subtraction of the viral vector. So, Got it. A significant part of it is the usual labor facilities and the raw materials. They're quite similar between the two technologies. Okay, that makes sense. We do have an audience question about kind of outlining the steps from tissue procurement to drug administration. Maybe you can kind of give an overview of that journey. So the steps from tissue procurement to drug administration. So the tissue is procured by the surgeon, and then that tissue is shipped to our manufacturing facility, basically, typically overnight or within the same day, depending on the location. Then we go through a 22-day, in the case of the commercial Amtagvi manufacturing process, and then the release testing using the potency matrix that we've worked with so long with the FDA and other release assays. And then, as I mentioned, typically at about day 34, the product is then shipped back to the Authorized Treatment Center. The product is cryopreserved, so it's frozen and can be administered to the patient when convenient. And some patients may come in the next day, some of them have family or other preferences. So the product arrives at the ATC, then the patient undergoes non-myeloablative lymphodepletion to prepare their immune system, basically remove the immunosuppressive tumor microenvironment. And then the patient receives an infusion of Amtagvi or other TIL in case of clinical products, and then receives several cycles of IL-2, which is about less than one-sixth of a dose of the old-fashioned high-dose IL-2, and then released from the hospital shortly after that. So it's a one-time therapy. That's the typical process. Yeah. Great. That makes a lot of sense. And I imagine aiming for a similar workflow for other programs in, let's say, lung cancer and in different indications. Is that kind of the vision? Of the lung cancer, the program that's in the pivotal trial uses exactly the same manufacturing process. Mm-hmm. What we're working on is, as part of the continuous improvement, shortening that whole workflow looking to reduce the time required, for example, for release testing, and as we scale up the volume, get the product back to the patient sooner. That's great. That makes sense. So we're just about at time, so I will thank you again, Igor, for building our questions and for all the insights that you've shared here. Congrats a gain, we appreciate it. Thank you very much. Thank you.